Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides

ABSTRACT

This invention relates to novel copolymers containing carbonate repeat units and ester repeat units.

RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. Nos. 134,321 and 134,339, each filed Dec. 17, 1987.

FIELD OF THE INVENTION

This invention relates to totally and partially bioresorbable devicescapable of degrading into biologically innocuous components. Moreparticularly, this invention relates to such devices which arefabricated totally or in part from copolymers having recurring unitsderived from cyclic carbonates and from lactides.

BACKGROUND OF THE INVENTION

Polycarbonates have been known for a number of years. U.S. Pat. No.3,301,824 describes the preparation of carbonate homopolymers and randomcopolymers with cyclic lactones. While the patent generally disclosesthe polymers as having utility in the molding, coating, fiber andplasticizing fields, there is no appreciation whatsoever ofbiodegradable and/or bioresorbable devices composed in whole or in partof polycarbonate.

Non-bioresorbable synthetic permanent vascular grafts have beenavailable and are made of either Dacron (polyethylene terephthalate) ormicroporous Teflon (polytetrafluoroethylene). Various prostheses such asgrafts, and especially those of small diameters for use in coronarybypass procedures, must have certain properties. These propertiesinclude physical and mechanical compatibility with the vessel to whichthey are connected, suturability, compliancy, ability to withstandpressure and pressure fluctuations, and flexibility. Required propertiesalso include biocompatibility, sterilizability, and low toxicity,allergenicity, and mutagenicity. Still other required properties includeappropriate durability, both in terms of "shelf life" after fabricationand appropriate durability after implantation. Problems which arise froma mismatch of a native vessel and a prosthesis include dilatation whichmay result in aneurysm formation and anastomotic hyperplasia, kinkingand the like. Vascular grafts having internal diameters of 8 mm or moreand made of biodurable materials have so far been the only successfulprostheses for providing a conduit for maintaining continuous blood flowwhile inflicting a minimal hematologic trauma. Vascular grafts made ofDacron in current clinical use are constructed of knitted or wovenDacron fibers with open pores in the fabric which have to be closed ordiminished by preclotting before implantation. Such prostheses have beenused as vascular replacements, but only for the relatively largerarteries.

Bioresorbable polymers have been used in the fabrication of devices forimplantation in living tissue for several decades. Medical applicationof such polymers include absorbable sutures, haemostatic aids and,recently, intraosseous implants and slow-release drug delivery systems,to name but a few. Use of such polymers has been extended to tissueregeneration devices such as nerve channels, vascular grafts, spermducts, fallopian tube ducts and the like. To be effective, these devicesmust be made from materials that meet a wide range of biological,physical and chemical prerequisites. The material must be bioresorbableat least in part, nontoxic, noncarcinogenic, nonantigenic, and mustdemonstrate favorable mechanical properties such as flexibility,suturability in some cases, and amenability to custom fabrication.

Various polymers have been proposed for use in the fabrication ofbioresorbable medical devices. Examples of absorbable materials used innerve repair include collagen as disclosed by D. G. Kline and G. J.Hayes, "The Use of a Resorbable Wrapper for Peripheral Nerve Repair,Experimental Studies in Chimpanzees", J. Neurosurgery 21, 737 (1964).Artandi et al., U.S. Pat. No. 3,272,204 (1966) reports the use ofcollagen protheses that are reinforced with nonabsorbable fabrics. Thesearticles are intended to be placed permanently in a human body. However,one of the disadvantages inherent with collagenous materials, whetherutilized alone or in conjunction with biodurable materials, is theirpotential antigenicity.

Other biodegradable polymers of particular interest for medicalimplantation purposes are homopolymers and copolymers of glycolic acidand lactic acid. A nerve cuff in the form of a smooth, rigid tube hasbeen fabricated from a copolymer of lactic and glycolic acids [The Hand;10 (3) 259 (1978)]. European patent application No. 118-458-A disclosesbiodegradable materials used in organ protheses or artificial skin basedon poly-L-lactic acid and/or poly-DL-lactic acid and polyester orpolyether urethanes.

U.S. Pat. No. 4,481,353 discloses bioresorbable polyester polymers, andcomposites containing these polymers, that are also made up ofalpha-hydroxy carboxylic acids, in conjunction with Krebs cycledicarboxylic acids and aliphatic diols. These polyesters are useful infabricating nerve guidance channels as well as other surgical articlessuch as sutures and ligatures.

U.S. Pat. Nos. 4,243,775 and 4,429,080 disclose the use ofpolycarbonate-containing polymers in certain medical applications,especially sutures, ligatures and haemostatic devices. However, thisdisclosure is clearly limited only to "AB" and "ABA" type blockcopolymers where only the "B" block contains poly(trimethylenecarbonate) or a random copolymer of glycolide with trimethylenecarbonate and the "A" block is necessarily limited to glycolide. In thecopolymers of this patent, the dominant portion of the polymer is theglycolide component.

U.S. Pat. No. 4,157,437 discloses high molecular weight, fiber-formingcrystalline copolymers of lactide and glycolide which are disclosed asuseful in the preparation of absorbable surgical sutures. The copolymersof this patent contain from about 50 to 75 wt. % of recurring unitsderived from glycolide.

SUMMARY OF THE INVENTION

The present invention relates to a bioresorbable or biodurable medicaldevice fabricated totally or in part from a copolymer selected from thegroup consisting of copolymers having at least one type of recurringmonomeric units of the Structure I: ##STR1## and having at least onetype of recurring monomeric unit of the Structure II: ##STR2## wherein:n is from 1 to about 8; and

R₁ and R₂ are the same or different and are hydrogen, alkyl or phenylwith the proviso that when said copolymers are block copolymers at leastone of R₁ and R₂ is other than hydrogen.

The copolymers used in the practice of this invention exhibit variousphysical and morphological properties which enable their use in thefabrication of a large number of medical devices. The copolymers for usein the practice of this invention may be crystalline to semi-crystallineto amorphous having varying modulus and tensile strength, elasticity,pliability and bioresorption rates. The device may be implanted inhumans to aid in tissue regeneration, growth and/or healing, or may beused outside of the body but in contact with living tissue, bodilyfluids and/or blood without undue adverse impact on such tissue, fluidsand/or blood. For example, copolymers used in the practice of thisinvention are amorphous, soft and pliable materials having relativelyfast rates of bioresorbability which can be fabricated into solidmedical devices, thin films, coatings and the like where softness andpliability are necessary requirements for the efficacy of the device.Other copolymers used in this invention are elastomeric which allowtheir use in the fabrication of elastic fibers and medical devices,coatings, films and the like where certain elasticity is critical forefficacy. Still other of the copolymers of this invention arecrystalline which exhibit high modulus, high tensile strengh, andrelatively slow rate of bioresorption. These copolymers can beconveniently fabricated into medical devices and fibers where highstrength and relatively slow rate of bioresorption are critical.

The copolymers for use in the fabrication of the device of thisinvention exhibit controllable bioresorbability and biodegradationrates, blood compatability, and biocompatibility with living tissue.These copolymers also induce minimal inflammatory tissue reaction. Thebiodegradation of the copolymers used to fabricate most of thebiodegradable devices of this invention usually results in degradationproducts having a physiologically neutral or relatively neutral pH.Various properties of the copolymers used in the practice of thisinvention render devices made from the copolymers especially suitablefor medical applications including but not limited to fabrication of thebioresorbable medical devices, such as vascular grafts, coating andfilms, wound and skin covers, hemostatic aids, bone or dental repair,and the like.

As used herein, "biodurable" means that the device is substantially notbiodegradable or bioresorbable.

As used herein, "living system" is a living cell, animal or plant,whatever phylogenetic level in the plant or animal kingdom.

As used herein, "biologically innocuous components" are components whichmay be contacted or implanted into living systems without inducing anadverse reaction and/or components which may be metabolized by theliving systems.

As used herein, the term "biodegradable" means capable of being actedupon biochemically in general by living cells or organisms or part ofthese systems, including water, and broken down into chemical orbiochemical products.

As used herein, "medical device" is a device used within or without ahuman body or animal body to achieve certain medical benefits of goals.

As used herein, "bioresorbable" is capable of being broken down andmetabolized by a living system.

As used herein, the term "copolymer" is a homopolymer and/or copolymercollectively.

As used herein, "biocompatible" is the capability to exist or coexistinside or in close contact with the living systems without adverselyimpacting the system.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to medical devices. The medical devices ofthis invention may be totally or partially bioresorbable and/orbiodegradable or may be biodurable. The devices of the invention arefabricated totally or in part of at least one copolymer of thisinvention or a combination thereof. The device may be formed totally outof the copolymer of this invention, or may be formed partially of thecopolymer of this invention in which the body of the device is formed ofone or more other biodurable or bioresorbable materials coated with thecopolymers of this invention using such techniques as solution dippingand solution coating, or the device may be a layered device in which oneor more layers are formed from the copolymers of this invention. Theonly requirement is that the device is fabricated wholly or partiallyfrom at least one copolymer comprising at least one type of recurringmonomeric unit of each of Structures I and II.

The devices of this invention may take many forms and have varyingdegrees of bioresorbability and/or biodegradability, depending onintended use. For example, the devices of this invention may be solidarticles fabricated using conventional techniques for fabricating partsfrom thermoplastic polymers such as injection molding, melt extrusion,solution casting, solution extrusion, gel extrusion and the like, suchas an extruded hollow tubular nerve channel or extruded hollow vasculargraft, or a stent for use in angioplasty. The devices of this inventionmay also be fibrous devices constructed of woven or non-woven fabricmade of fibers formed from the copolymers of this invention. Forexample, the device of this invention may be fabricated from fibersand/or yarns which have been woven, braided and/or knitted into fabricshaving various structural configurations using conventional means, whichfabrics may then be used to fabricate a device, such as a wound cover,gauze, and a vascular graft coated with one or more copolymers of thisinvention.

Illustrative of useful devices of this invention are orthopedic andfracture fixation devices such as pins, clamps, screws, rods, maxillofacial repair implants, intraosseous implants, and plates; vascularimplants such as vascular grafts and vascular stents; wound closingdevice such as sutures, fasteners, clips and staples; nerve channels;and the like. Illustrative of still other devices within the scope ofthis invention are devices for tendon and ligament replacement, breastprostheses, wound and burn dressings, dental packs, sponges, herniapatches, absorbant swabs, fallopian tube and sperm ducts, drug-deliverydevices, and the like.

The rate of bioresorption and/or biodegradation exhibited by the deviceof this invention will vary depending on the desired longevity of thedevice. For example, because of the relatively high degree ofcompatibility between the copolymers used in the construction of thedevice of this invention and blood and tissue of living systems, onedevice of this invention is a conventional part which contacts blood,other bodily fluids, or living tissue such as tubing of anextracorporeal loop or other types of flow-through systems for blood,bodily fluids, heart valves and the like. In such instances, the deviceshould be formed or at least have a surface which will contact theblood, bodily fluids, and/or the living tissue coated with a copolymerhaving a relatively slow rate of bioresorbability and/orbiodegradeability or which is even relatively biodurable. On the otherhand, another device of this invention is a vascular graft composed of afabric composed of a relatively biodurable material such as Dacron or abioresorbable copolymer having a relatively slow rate of bioresorptioncoated with a relatively fast bioresorbing copolymer, especially in theinside of the graft. The use of the coating having fast rate ofbioresorption provides for a regenerated blood vessel having a highdegree of patency and relatively low rate of thrombosis.

In one preferred embodiment of this invention, the devices are composedof solid articles which are fabricated from the copolymers through useof conventional techniques such as injection molding, gel or meltextrusion and the like for fabricating solid articles from thermoplasticpolymers. These techniques are well known in the art and will not bedescribed herein in any great detail. For example, such techniques aredescribed in Encyclopedia of Polymer Science and TechnologyInterScience, New York. The preferred solid devices of this inventionare relatively biodurable tubing and coatings which will contact theblood or tissue of a living system, biresorbable and/or biodegradableorthopedic pins, rods and plates, extruded wound and burn coverings,extruded nerve growth channels, extruded fibers for use in tendon andligament repair and the like.

In another preferred embodiment of the invention, the devices arefibrous devices fabricated totally from fibers composed of thecopolymers of this invention. The fibers, which are also devices of thisinvention, are prepared by any suitable fiber-forming technique, and thefibers can then be fabricated into useful medical devices usingconventional techniques. For example, fibers made from the copolymersmay be formed by conventional processes such as spinning techniques,including melt, solution, dry and gel spinning. Illustrative of suitablefiber spinning processes and melt spinning techniques and apparatus forcarrying out these processes are those described in "Man Made FibersScience and Technology", Vol. 1-3, H. F. Mark et al., Interscience NewYork, 1968; "Encyclopedia of Polymer Science and Technology", Vol. 3;Fundamentals of Fiber Formation by Androzej Ziabuke, Wiley and Sons, NewYork, New York (1976); and "Encyclopedia of Polymer Science andTechnology", Vol. 3, pps. 326-381.

Preferred implantable bioresorbable medical devices are vascularimplants, nerve channels; burn and wound covers; facial substitutes;orthopedic substitutes for bone or bone repair; breast prostheses;tendon and ligament replacements; hernia patches; and the like, or usedas sutures and fasteners. Other devices not necessary for implantationpurposes can also be formed from the fibers of this invention. Thedevices include cell culture substrates, absorbants or swabs, medicateddressings, gauze, fabric, sheet, felt or sponge for hemostasis, dentalpacks and the like. Particularly useful devices are woven or knittedfabrics formed into tubes of varying shapes, lengths and diameters.Illustrative of these devices are tubular prostheses such as vasculargrafts, nerve guidance channels and the like. The particularconfiguration of such tubes may vary according to the size and shape ofthe organ to be repaired, and whether the intended repair is to takeplace in human surgery or in surgery involving other animal species.

Other preferred devices of this invention are those which are useful inligament and tendon replacements. These devices are usually constructedof a fiber-like body composed of a relatively biodurable material suchas ceramic fibers, graphite, polyethylene and the like coated with abioresorbable or biodegradable copolymer. Organized tissue formation isencouraged by the use of the composites of this invention, which aids inregenerating ligaments and tendons.

Yet other preferred devices of the invention are those which are usefulin dental and orthopedic repair. In this application, the dental andorthopedic repair devices may be used in composite structures with orwithout such materials as calcium hydroxyapatite, glassy calciumphosphate, Bioglass, calcium triphosphate, drugs, and the like.

Still other preferred embodiments are devices for use as drug deliverysystem. Such drugs include drugs for control of body functions such asbirth control and other medicinal drugs. In these embodiments, the drugcan be dispersed in a bioresorbable copolymer matrix having abioresorption rate such that the desired quantity of drug is releasedinto body as a function of time.

Other preferred devices of this invention are hollow fibers which areparticularly suited for use as nerve channels for the repair of severednerves formed from the copolymers by any conventional technique such assolution dipping on a mandrel, melt extrusion, solution extrusion, gelextrusion, and the like. The diameters of the nerve channels will varyaccording to the size and shape of the nerve to be repaired. U.S. Pat.No. 3,833,002 discloses various sizes and shapes that may be employed.Lengths of the hollow fibers or tubes and their internal diameters andwall thicknesses will also vary according to intended use. The length ofthe hollow fiber or tube is usually sufficient to bridge the size of thegap to be repaired and to allow extra tubing in which to insert nervestumps. Particularly useful internal diameters commonly range from about0.13 mm to about 5.00 mm. Particularly useful wall thicknesses areusually from about 0.01 mm to about 3.0 mm, and preferably from about0.05 mm to about 1.5 mm.

The devices of this invention are fabricated totally or in part fromcopolymers having at least one type of recurring monomeric unit of theStructure I: ##STR3## and at least one type of recurring monomeric unitof the Structure II: ##STR4## wherein R₁, R₂, and n are as describedabove.

Illustrative of recurring monomeric units of the Structure I aretrimethylene carbonate, tetramethylene carbonate, pentamethylenecarbonate, hexamethylene carbonate and the like. Illustrative ofrecurring monomeric units of the Structure II are those derived fromsubstituted and unsubstituted dilactones such as those of the formula:##STR5## wherein R₁ and R₂ are as described above. Such dilactonesinclude lactides such as l-lactide, d-lactide, and d,l-lactide andlactones and dilactones such as those derived from 2-hydroxycarboxylicacids such as 2-hydroxybutyric acid, 2-hydroxy-2-phenyl-propanoic acid,2-hydroxy-4-methylpentanoic acid, 2-hydroxyhexanoic acid,2-hydroxyoctanoic acid, and the like.

Preferred for use in the practice of this invention are devices formedtotally or in part from copolymers formed from at least one type ofrecurring unit of the Structure I wherein:

n is 1, 2, 3, 4 or 5; and where monomeric units of the Structure II arederived from l-lactide, d,l-lactide, d-lactide, 2-hydroxybutyric acid or2-hydroxy-2-phenylpropanoic acid.

In the most preferred embodiments of this invention, the device isformed totally or in part from copolymers comprising at least one typeof recurring monomeric unit of the Structure I: ##STR6## wherein n is 1,2 or 3 and comprising at least one type of recurring monomeric units ofthe Structure II derived from l-lactide, d,l-lactide or d-lactide.

Copolymers for use in the fabrication of the device of this inventioncan be random copolymers or may be block copolymers depending on theproperties of the polymer required for the particular application.Illustrative of useful copolymers are random copolymers comprising oneor more monomeric units of each of the Structures I or II. Alsoillustrative of copolymers useful in the fabrication of the device ofthis invention are block copolymers comprising one or more "B" blockswhich may be formed of recurring units of Structure I and one or more"A" blocks which may be formed from one or more recurring units ofStructure II. Each "A" block and each "B" block may be the same ordifferent. As used herein, the term "block" means a sequence of one typeof monomeric unit at least about 5 monomeric units long, or suchsequence of two or more types of recurring monomeric units eitherrandomly distributed in such a sequence or distributed such sequence ina block-like fashion. Each "A" block and "B" block may comprise a singletype of recurring monomeric unit. Alternatively, each block may comprisemore than one type of recurring monomeric unit, randomly distributedthroughout each block. For example, the block copolymers as describedabove may have repeating block units such as AB, ABA, BAB, ABAB, ABABA,BABAB, and the like, where each "A" block and each "B" block containsthe same or substantially the same types of recurring monomeric unit,and/or where each block contains the same or substantially the samenumber of recurring units. Alternatively, the various "A" and "B" blockscontained in the block copolymers may have more than one type of "A"block or "B" block, each of which may contain a different type or typesof recurring monomeric units; or each block may contain the same ordifferent types of recurring units but have differing number ofrecurring units in each block. With respect to the recurring blocks ofA's and B's, each of them may also be the same or different. Forexample, ABABA may in fact be MNOPQ, ABA may be MNQ or ABA may be MNOPQ,where M, N, O, P and Q are the same or different provided that at leastone of M, N, O, P and Q is a recurring unit of the Structure I or II.

In some preferred embodiments of this invention where soft, pliable andrelatively fast bioresorbing materials are required as for example incoatings and the like, the polymer of choice is a random copolymer. Inother preferred embodiments of this invention where hard, crystallineand relatively slow bioresorbing materials are required as for exampleorthopedic and fracture-fixation devices, the copolymers of choice areblock copolymers. Especially preferred are block copolymers ofstructures AB and ABA, with ABA being the most preferred. Through use ofselected monomeric units and their arrangement in the polymer chain,thermal history, mechanical processing and treatment of the copolymerand the devices fabricated from the devices, the properties of thecopolymer such as elasticity, modulus, pliability, hardness, softnessand crystallinity, and the bioresorption rate of the copolymer can betailored and optimized for any particular application.

The types of recurring monomeric units and molecular weight of thecopolymer, as well as the relative percentages of each of the recurringmonomeric units in the copolymers used in the fabrication of the deviceof the invention may vary widely depending on the particular device andthe desired characteristics of the copolymer or homopolymer. The typesand quantities of recurring units and the molecular weight impact on thephysical properties of the copolymer such as tensile strengh, modulus,hardness, elasticity, softness, toughness, compliancy, crystallinity,bioresorption rate and the like as needed for optimized or at leastacceptable performance of the device. These properties in turn, will bedeterminative of the characteristics of the device and the suitabilityand efficacy for use in any application. Various types and amounts ofrecurring monomeric units can be conveniently selected to tailor theproperties of the copolymer to optimize the desirable propertiesrequired for any device.

While we do not wish to be bound by any theory, it is believed thatwhether it is random or block copolymers, the higher the content ofmonomeric units of the Structure I the more flexible and soft thecopolymer will be. Conversely, in such random or block copolymers, thehigher the content of monomeric units of the Structure II, the morecrystalline and hard the copolymer. With respect to biodegradation orbioresorption, the higher the crystallinity, the slower the rate ofbioresorption or degradation. For example, soft, pliable and relativelyfast bioresorbing coatings and devices can be obtained from a 90:10random copolymer or trimethylene carbonate and lactide and 95:5 blockcopolymer of trimethylene carbonate and lactide. In other situationswhere toughness and a slower bioresorption rate is desired as forexample in a stent, a tendon or ligament replacement device, orthopedicplates and pins, monomeric units such as those of the Structure II areselected and incorporated into the copolymer in a major amount. Forexample, hard and crystalline devices can be obtained from a 85:15 blockcopolymer l-lactide/trimethylene carbonate/l-lactide.

The preferred embodiments of this invention where the desired materialis soft, pliable and relatively fast bioresorbing recurring units of theStructure I are in the "major amount". As used herein, "major amount" ismore than about 50 weight % based on the total weight of all recurringmonomeric units in the copolymer. In the preferred embodiments of theinvention, the amount of recurring units of Structure I may range fromgreater than about 50 wt. % to less than about 100 wt. %, based on thetotal weight of recurring units in the copolymer, preferably from about80 wt. % to less than about 100 wt. %, and most preferably from about 90wt. % to about 99 wt. %.

The preferred embodiments of this invention where the desired materialis hard, crystalline and relatively slow bioresorbing recurring units ofthe Structure II are in the "major amount". As used herein, "majoramount" is more than about 50 weight % based on the total weight of allrecurring monomeric units in the copolymer. In the preferred embodimentsof the invention, the amount of recurring units of Structure II mayrange from greater than about 50 wt. % to less than about 100 wt. %,based on the total weight of recurring units in the copolymer,preferably from about 80 wt. % to less than about 100 wt. %, and mostpreferably from about 90 wt. % to about 99 wt. %.

Useful average molecular weight ranges of copolymers for use in anyparticular situation will vary depending on the desired characteristicsof the copolymer. In general, physical properties such as modulus,tensile strength, crystallinity and the like require a certain minimummolecular weight, which will vary with each copolymer. Above thisminimum, the properties do not depend strongly on molecular weight. Meltviscosity and solution viscosity increase with increasing molecularweight useful for a particular polymer. For this reason, there usuallywill be a maximum molecular weight because of the difficulty ofprocessing it into the desired articles by conventional technology.Within the range of useful molecular weights, the rate of bioresorptionwill vary with the molecular weight and the crystallinity of thecopolymer. Higher molecular weight and more crystalline copolymers willrequire longer times to bioresorb. The desired length of duration of thedevice will bioresorb will dictate the choice of molecular weight.

In general, the devices of this invention are formed totally or in partof copolymers having at least one type of recurring monomeric units ofStructure I and II that can range in molecular weight from low molecularweight to extremely high molecular weight. Molecular weights ofcopolymers for use in the practice of this invention usually are equalto or greater than about 3,000. Preferred average molecular weightranges are from about 7,000 to about 5,000,000, with a range of fromabout 10,000 to about 500,000 being particularly preferred, and a rangeof from about 15,000 to about 250,000 being most preferred.

Other components may be combined with the copolymers before they areformed into the devices of the invention, or added to, coated onto andthe like, during or after their formation. These components includesubstances that will not interfere with the desired properties of thecopolymers, e.g., their ability to degrade into components biologicallyinnocuous to living systems. Among the contemplated classes of suchsubstances are placticizers, stabilizers for UV or temperature,pigments, lubricants and antioxidants. One of skill in the art willappreciate that any additives included in the medical devices of theinvention, should be those that would meet with FDA approval.

Other optional polymeric components, either bioresorbable or biodurable,such as fibers, fillers and binders may be combined with the copolymersprior to and during the formation the devices, or subsequent to theirformation. These include, but are not limited to polymers and copolymersselected from the group consisting of polyesters such as poly(butyleneterephthalate) and poly(ethylene terephthalate); poly(vinyl alcohol);poly(vinyl acetate) and partially hydrolyzed forms thereof; hydrogeltype polymers such as poly(hydroxyethyl methacrylate),poly(hydroxypropyl methacrylate), and the like; polysulfones such aspoly(phenylenesulfone); carbon; silicon carbide; halopolymers such aspoly(tetrafluoroethylene), ethylene/tetrafluoroethylene copolymer andthe like; poly(dioxanone); poly(glycolide-co-trimethylene carbonates);poly(lactides); poly(d-lactide); poly(l-lactide);poly(lactide-co-caprolactone); poly(d,l-lactide); poly(caprolactones);poly(hydroxybutyrates); poly(hydroxyvalerates);poly(hydroxybutyrate-co-hydroxyvalerates); poly(glycolide);poly(urethanes); segmented poly(urethanes); poly(etherurethanes);poly(urethane ureas); silicone rubber; and substances such as fibrin andits powder; natural or processed collagen; mono-, di-, tri-, andpoly(saccharides); poly(ethylenes); poly(amides); poly(propylene);peptides such as nerve growth factors, bone growth factors, laminin, andthe like; poly(carbonates); poly(vinyl fluoride); poly(vinylidenefluoride); poly(vinyl butyral); cellulose such as, carboxylmethylcellulose, cellulose acetate, ethylcellulose, and the like; ethylenevinylacetate copolymers and hydrolyzed and partially hydrolyzed formsthereof; poly(acrylonitrile); poly(vinyl methyl ether); and theirderivative copolymers, blends, composites, and the like.

Other biocompatible components besides polymeric components may becombined with the polymers during or before they are formed into thedevices of the invention, or added to, coated onto and the like, aftertheir formation. These components include substances that will enhancecertain of the desired properties of devices made from the copolymers.Illustrative of such substances are plasticizers, lubricants,antioxidants, stabilizers of all kinds such as stabilizers for UVradiation, heat, moisture, and the like, as well as drugs for treatmentof certain disorders or diseases and growth factors such as those fornerve, bone, and growth hormones in general. Materials such as calciumphosphates, ceramics, bioresorbable or otherwise, such as calciumhydroxyapatite, Bioglass, and calcium triphosphate may also be combinedwith the polymer. Components such as certain barium salts to renderdevices formed with them radio-opaque are also within the contemplationof the invention. Certain of these fillers, binders, additives andcomponents can be removed or leached from such copolymers contained inthe devices at some stage, so that a porous or semi-porous system can beobtained.

The devices of this invention may also include other bioresorbablematerials. Illustrative of such materials are those described in U.S.Pat. Nos. 4,052,988; 4,157,437; 4,190,720; and 4,429,080 and thematerials described in U.S. patent application Ser. Nos. 134,321, filedDec. 17, 1987 and 134,339, filed Dec. 17, 1987.

Devices of this invention may be fabricated totally from the copolymersof the Structure I or II or may be fabricated in part from otherbioresorbable materials or from biodurable materials which arerelatively resistant to biodegradation. Illustrative of biodurablematerials useful in the fabrication of devices of this invention aresilicone, silicone rubber, poly(ethylene), poly(ethylene terephthalate),poly(fluoroethylene), poly(phosphazene), poly(urethane), segmentedpoly(urethane), and the like. Also useful are biodurable metallicsubstances such as titanium, stainless steel, and alloys such aschrominium-cobalt-molybelenum alloys, titanium-aluminum-vanadium alloys,and the like.

The following are more specific examples of various embodiments of theinvention and are not to be considered limitative thereof.

EXAMPLE 1 Synthesis of 1,3-Dioxan-2-one (Trimethylene Carbonate (TMC))

A 1-liter three-neck round bottom flask was fitted with mechanicalstirrer and a 12 in. Vigreux column topped with a distilling head havinga stopcock for controlling the reflux ratio. The flask was charged with1,3-propanediol (228.3 g, 3 mol) and diethyl carbonate (454 mL, 3.75mol), flushed with nitrogen, then immersed in an oil bath. Heating wasinitiated and, when the temperature had reached about 80° C., sodiummethoxide (1.62 g, 30 mmol) was added via funnel through the third neck.The oil temperature was raised to 155°-160° C., and ethanol soon beganto reflux.

Ethanol was removed gradually over a period of about 3.5 hrs. underpartial reflux. Takeoff cannot be too fast, as the temperature risesfrom about 80° C. as the distillate becomes rich in diethyl carbonate. Atotal of 268 grams of distillate was collected, with about 80-85%ethanol and the remainder carbonate by NMR. Additional sodium methoxide(0.40 g, 7.4 mmol) was cautiously added at this point and heating wascontinued for another 30 mins. A slight vacuum was carefully applied,and additional distillate collected. The vacuum was gradually increaseduntil the pressure was down to about 1 mm, by which time most of theremaining diethyl carbonate was removed.

The oil bath was lowered and stirring continued for about 15 min.(temperature was not monitored). Triethylamine hydrochloride (5.2 g, 38mmol) was added and stirring continued for 45 min. without heating.Stannous octoate (15 drops, about 0.2 grams) was added, heating resumed(bath at 150° C. initially, increasing to 200° C.), and a vacuumgradually applied to about 0.5 mm. An initial forecut boiling 70°-125°C. (25 g) was rejected, while the main fraction (245 g) collected at125°-135° C. (0,5 mm) was about 85% pure by NMR. The residue from thedistillation was dissolved in chloroform, filtered and distilled in aKugelrohr at 160°-220° C. (0.1 mm) to give an additional 25 grams ofdioxanone.

The main fraction was recrystallized from 1:1 ether: THF (4 mL/g) togive 168 g of dioxanone of high purity. Evaporation of the filtrate andtrituration with ether-THF (about 4:1) gave an additional 45 g of crudeproduct, which was combined with the 25 grams obtained from cracking ofthe residue. Recrystallization from ether-THF gave 46.5 g of puredioxanone. The combined 214.5 grams of dioxanone was distilled in theKugelrohr at 120°-130° C. (0.1 mm) to give 209.3 g (68% of theory)polymer grade product.

EXAMPLE 2 Poly (TMC-co-l-Lactide).

Freshly distilled trimethylene carbonate (12.95 g, 127 mmol) was meltedtogether with dried, recrystallized l-lactide (2.03 g, 14.1 mmol), thenthe mixture was syringed into a 15 mL polymerization tube. The catalyst(73 μL of 3.0×10⁻² M stannous octoate in toluene) was added, then thetube was degassed by freezing, pumping and thawing twice. After sealingunder vacuum, the tube was immersed in an oil bath at 160° C. for 60hours. The tube was cracked and 10 g of the crude polymer was dissolvedin chloroform (250 mL), then precipitated into isopropanol. The driedpolymer, 8.6 g, had a reduced viscosity of 1.53 dL/g (0.1% solution indioxane).

In another experiment, freshly distilled trimethylene carbonate (12.95g), 2.03 grams of recrystallized L-lactide and 7.5 μL of 1.0M stannousoctoate in toluene was placed inside a 160° C. oil bath for 16 hrs. Theampule was cracked and 12.9 grams was the final yield after twicereprecipitated from tetrahydrofuran (THF) solution. The weight averagemolecular weight was 87,000 and number average molecular weight was13,760 by GPC in THF. The GPC system was calibrated with polystyrenestandards.

EXAMPLE 3 ABA Block Copolymer of Trimethylene Carbonate (TMC),d,l-lactic Acid (d,l-LA) and l-lactic Acid (l-LA).

An oven-dried, silanized glass 100 mL resin flask was equipped withmechanical stirrer and a glass paddle, argon inlet, a serum cap on oneport, and a glass stopper on the remaining port. To the flask were addedfreshly dried and purified TMC (19.80 g, 194 mmol), d,l-Lactide (2.20 g,15.3 mmol), and 2,2-dimethyl-1-3-propanediol (27 mg, 0.26 mmol). Theflask was evacuated and filled with argon several times, then immersedin an oil bath at 150° C. Stirring was initiated, and after 5 minutes,40 μL of a 1.0M solution of stannous octoate in toluene was added.

After one hour, a sample of the viscous polymer was removed andl-Lactide (9.43 g, 65.4 mmol) was added through one port. Stirring wasstopped after one hr., then heating stopped after an additional hr. Thepolymer was removed from the flask, dissolved in tetrahydrofuran (250mL), precipitated into methanol (750 mL), and dried under vacuum at 50°C. Yield: 23.2 g (74%). Weight average molecular weight (relative topolysytrene standards) of the prepolymer=57,000; of the finalpolymer=107,000. Proton NMR analysis of the final polymer shows a TMCcontent of 50 mole percent (theoretical=55%). From the methine region ofthe proton NMR, one can estimate that about 74% of the lactic acid unitsare connected to other lactic acid units, compared to a theoreticalvalue of 89.5% for a totally random B block and a totally homopolymer Ablock.

Similarly, two experiments were performed using this method to prepareother such block copolymers:

    __________________________________________________________________________    ABA BLOCK COPOLYMERS OF TRIMETHYLENE CARBONATE (TMC),                         d, l-lactic acid (d, l-LA) and l-lactic acid (l-LA)                           __________________________________________________________________________    Sample                                                                              A     B        A:B    Quantity                                          No.   Block Block    Ratio  Isolated                                                                           Yield (%)                                    __________________________________________________________________________    1     l-LA  TMC:d,l-LA 9:1                                                                         30:70  21.2 g                                                                             78                                           2     l-LA  TMC:d,l-LA 7.3:1                                                                       36:64  22.0 g                                                                             72                                           3     l-LA  TMC:d,l-LA 1:1                                                                         33:67  19.8 g                                                                             80                                           __________________________________________________________________________    Sample                                                                            GPC Main Peak                                                                           GPC Overall        % TMC by NMR                                 No. Wt Av MW                                                                             Disp.                                                                            Wt Av Mw                                                                             Disp                                                                             Tg   Tm  (Theory)                                     __________________________________________________________________________    1   94,000 2.64                                                                             120,900                                                                              24.8                                                                             -5° C.                                                                      150° C.                                                                    63(63)                                       2   86,800 1.72                                                                             80,800 1.72                                                                             -10° C.                                                                     156° C.                                                                    56(55)                                       3   50,000 3.60                                                                             68,000 16.0                                                                             17° C.                                                                      124° C.                                                                    31(33)                                       __________________________________________________________________________

EXAMPLE 4 Trimethylene Carbonate/l-Lactide [90/10] Random Copolymer

In a 100 mL reaction flask fitted with mechanical stirrer and argoninlet were combined trimethylene carbonate (51.45 g, 504 mmol),l-lactide (8.07 g, 56 mmol), and 1,6-hexanediol (47 mg, 0.40 mmol). Theflask was evacuated and filled with argon several times, immersed in anoil bath at 160° C. and stirring was initiated. After 10 mins., thepolymerization catalyst, 25 μL of 0.20M solution of tin(II) octoate intoluene, was added via syringe. The mixture was stirred at 160° C. for 4hrs., then the polymer was removed from the flask, dissolved intetrahydrofuran (450 mL), and precipitated into methanol (1200 mL) in ablender. The precipitated polymer was stirred with additional methanol(400 mL) in the blender, filtered, and dried in the vacuum oven at 50°C. Yield: 43.8 g (74%). Weight average molecular weight=120,000(polydispersity 1.5). Proton NMR (400 MHz) shows a final composition of80% trimethylene carbonate units and 20% lactic acid units (theroetical82% and 18%, respectively). This polymer is especially useful as acoating polymer.

EXAMPLE 5 Completely Bioresorbable Crimped and Coated Graft

1. Totally bioresorbable 6 mm vascular grafts were woven from fibers ofrandom copolymers of 97.5% 2,2-dimethyltrimethylene carbonate (DMTMC)and 2.5% TMC, and from fibers of random copolymers of 98.2% DMTMC and1.8% caprolactone.

2. Weaving: The 200 denier fiber was twisted 7.125 turn/inch whenrepackaged, to be used for the filling (horizontal) and wrap (vertical)construction to keep the monofilaments together. The fabrics were aplain weave tube with both warp and fill directions having the samefiber, at a construction of 120 total body ends by 120 picks per inch(that is a perfect square, tight weave). The total circumferences were18.8 and 25.2 mm for each of the fibers used, which correspond to 6 and8 mm diameter respectively. Some obviously defective areas were foundfrom time to time due to slight changes of tension on the fill bobbin,and also due to the knots in the towed fiber.

3. Crimping according to the general method of Jekel (U.S. Pat. No.3,337,673) was used. Thus, the spacer was provided by a cotton stringhelically wound on the fabric graft body with a glass mandrel insertedinto the lumen. Crimp-shape was formed by slowly forcing the two ends ofthe graft towards the middle. The crimping can be set to as small as 0.5millimeter up and 0.1 to 0.2 mm down so that the internal surfaceappears to be almost smooth but still resist kinking. Afterheat-setting, cleaning was done according to section 4 of Example 29.

4. A solution containing 2 to 3% coating polymer, e.g., the randomcopolymer of 91% TMC-9% l-lactide, was made with solvent dimethylsulfoxide (DMSO). The clean bioresorbable graft was dipped into saidsolution six dips, inverting between each dip, to yield a 10% weightgain. In another example, when a 4.5% coating solution was used, 25%weight gain was obtained after nine dips. The dipping was performedinside a Class 100 laminar flow hood.

5. Standard room temperature cycle ethylene oxide was used to sterilizethese completely bioresorbable coated and crimped vascular grafts.

6. The water permeation rates at 120 mm Hg pressure of such prostheseswere about 400 cc/cm² minute. They were implanted bilaterally in sheepas carotid replacements without preclotting. No complication resulted.The patency rate at 12-week stands at 100% (6 out of 6 grafts) for these6 mm, totally bioresorbable, crimped and coated vascular grafts.

EXAMPLE 6

Eight 8 centimeter long pieces of human-implantable grade, crimped USCISauvage Bionit, vascular grafts manufactured by C. R. Bard, having a sixmillimeter diameter, were ultrasonicated with 0.05% Triton X-100 in 1:1alcohol/water for sixty minutes at room temperature. The vascularprotheses were then rinsed several times with deionized water, followedby two rinses with 95% ethanol and drying in a laminar blow hoodequipped with high efficiency air filters. The dried vascular graftswere immersed into a solution of 1.40 grams of double-precipitatedrandom copolymer of 91% TMC-9% l-lactide (approx. 87,000 Daltons weightaverage molecular weight) in 140 mL of tetrahydrofuran, THF. Thevascular grafts were inverted after each dip, allowed to dry, and weightuntil the desirable weight gains were attained. A total of seven dipswere performed for a 25% weight-gain. The dipping and packaging wereperformed inside the laminar flow hood. The protheses were subjected toroom temperature ethylene oxide sterilization. The water permeation ratedecreased from 1,500 to below 200 cc/cm² min. after the coating.

Under anethesia, light anticoagulation (during implantation) and sterileoperating room conditions, two vascular grafts were implanted byend-to-end anastomoses without preclotting into both the left and rightexternal carotid arteries of each of the four adult domestic femalesheep weighting approx. 50 kilograms.

After seven weeks, one of the four sheep was electively terminated andboth grafts were patent and displayed pearl-like neointimal surfaces.The remaining three animals were kept to twelve weeks and electivelyterminated so as to be able to be compared to the control described inExample 31. All six excised grafts were patent and the blood contactingsurfaces displayed smooth translucent pseudoneointimal layers.

Control Experiment. For comparison, the same procedure was performedwith the Sauvage Bionit graft as received without coating. However, thegrafts were preclotted just prior to insertion, a standard procedureused to diminish bleeding as suggested by the manufacturer. The patencyrate was 15 out of 18 (83.33%). All luminar surfaces of the implantswere covered with a much thicker layer of internal capsule and redthrombus as compared to the coated grafts described above.

EXAMPLE 7

Similar to Example 6, four similar eight centimeter long six millimeterdiameter Sauvage Bionit vascular graft with the same coating polymer but50% weight gain were implanted in two adult sheep as bilateral carotidreplacements. One was electively terminated at seven weeks and the otherat twelve weeks. All four excised grafts were patent at termination withpearl-like blood contacting surfaces.

EXAMPLE 8

Fibers obtained from a random copolymer of 97.5% DMTMC and 2.5% TMC weretowed to 180 denier and woven into six millimeter tubular fabric with120 body ends per inch by 120 picks per inch. The fabric was crimped byfirst wrapping a cotton thread spirally around the tubular fabricsupported with a pyrex glass rod as a mendrel, then compressed andheat-set at approx. 80° C. The experimental grafts were cleaned aspreviously described. The grafts were further coated with the randomcopolymer of 91% TMC and 9% L-lactide from a 2 wt. % solution indimethylsulfoxide which dissolved the coating copolymer but not thefabric fiber. The water permeation rates dropped from 300 cc/cm² min. toabout zero after coating. A total of fourteen eight centimeter long sixmillimeter diameter completely bioresorbable vascular grafts, crimpedand coated with 10% wt-gain, were implanted as bilateral carotidreplacements in adult sheep as described in Example 6. One sheep diedacutely (never recovered from anesthesia) for reasons unrelated to thegrafts, as both grafts and the suture-lines were all intact. Fiveanimals were kept to twelve weeks post operation and electivelyterminated. All ten excised vascular grafts were patent. The last animalwas electively terminated after 24 weeks and both of the excised graftswere patent.

EXAMPLE 9

As in Example 8, six mm diameter vascular grafts were woven from yarnsextruded from random copolymer with 95.6% DMTMC and 4.4% caprolactone.It was crimped, cleaned, coated and sterilized as described. A pair ofsuch grafts, with 10% coating (copolymer of 91% TMC and 9% L-lactide)were implanted under sterile conditions, as described, into an adultsheep as bilateral carotid replacements. After eight weeks indwelling,the animal was electively terminated and the excised grafts were patentand the neointimal surfaces were thin and pearllike.

EXAMPLE 10

Six Weavenit Dacron (Meadox Medical), crimped human implantable vasculargrafts (4 mm diameter, 4 cm in length) were coated to 10% weight-gainwith random copolymer of 91% TMC and 9% L-lactide in tetrahydrofuransolution. Water permeation rate dropped from 1,500 cc/cm² min. to 175cc/cm² min when coating was equal to 10% of the initial weight. The leakrate was considered to be tolerable without preclotting. Aftersterilization, they were implanted as carotid replacements in threemongrel dogs weighing approximately 22 kilograms each. Each dog receiveddipyridamole (25 mg) and aspirin (325 mg) beginning at 4 dayspreoperatively and continued for 2 weeks post-operatively so as tominimize the effect of sugery. All three animals were electivelyterminated at 4 weeks postoperatively (i.e., the subjects were withantiplatelet treatment for two weeks followed by two without suchtreatment). Four of the six grafts were found to be patent.

EXAMPLE 11

Similar to Example 10, four such Weavenit four millimeter diametergrafts were coated with the copolymer of 91% TMC and 9% L-lactide to 25%weight-gain. The water leakage rate dropped from 1500 cc/cm² min toalmost zero. The grafts were implanted into two mongrel dogs given thesame antiplatelet treatment for the pre- and post-operative periods. Atfour weeks post-operation, both animals were electively terminated andthe four excised grafts were found to be patent.

EXAMPLE 12 Suture Fabrication

1. Using a 0.030" round hole die, ABA block copolymer of l-lactideA-block and TMC d,l-lactide (90/10) B-block with A and B approximately50% the modified Instron as an extruder, fibers are extruded at 220° C.The fibers are further drawn close to the maximum and are held at thatlength to set. The fibers can be used as synthetic sutures.

2. Sutures and fibers from the above example can also be coated,multiplied or braided to be used in areas where higher mechanicalstrength, softer texture or better knot holding capability is desired.

EXAMPLE 13 Nerve Channel Extrusion

The fabrication of polycarbonates biopolymers to nerve channels, tubes,or hollow fibers based on l-lactide - TMC type of copolymers in an ABAor BAB triblock structure where A is l-lactide hard block and B, therubbery block, is a copolymer of TMC with or without lactides, wasevaluated using the Instron Rheometer as a ram extruder and a tube inorifice type die. The hollow fiber or tube dimensions were controlled bythe die dimensions, differential gas pressure between the inner andouter surfaces of the tube, melt draw down and subsequent orientationprocesses. Range of diameters was about 0.5 to about 3 mm internaldiameter, with significant wall thickness to provide rigidity andstrength for implantation into an animal or human.

Dies having the outer diameters of the center tube of about 1.5 mm andorifices ranging from 2.5-3.5 mm were used without an appreciableapplied pressure differential. There was significant die swell duringextrusion which provided inner tube diameters greater than 3 mm. Otherdesirable diameters were easily achieved by drawing.

EXAMPLE 14 Nerve Channel Fabrication via Solution Dipping

Samples ranging from 0.5 mm I.D.×0.75 mm O.D. to 3.0 mm I.D.×3.50 mmO.D. were routinely prepared by this method for use as nerve channels.

a. Mandrel materials included, e.g., Pyrex glass tubings or rods,stainless steel (316) tubings or rods, platinum wires and tungsten wiresor rods. They were selected partly because of their higher surfaceenergy so that the polymer solution would spread evenly on theirsurfaces and partly because they were relatively inert so they can becleaned easily and reused.

b. Solvents: Usually tetrahydrofuran and a few drops methyl ethyl ketoneor methyl isobutyl ketone. Occasionally, chloroform or 1,4-dioxane wasused as the primary solvent depending on the solubility of the polymersystem.

c. Polymer solutions ranging from 1% to 15% by weight to solvent volumeratio have been used and the concentration was adjusted so that between8 to 20 dips would give the desirable wall thickness. (The rule of thumbis that the larger the diameter, the thicker the wall will be needed toavoid collapsing. Therefore, either more dips would be required or aslightly more concentrate solution could be used.)

d. Time between dips was usually ten to thirty minutes. For a fewpolymer systems, the wall contracted after overnight drying. Thus, anadditional one or two dips had to be performed the following morning,i.e., 15 to 16 hours later.

e. Molecular weight of polymer used (weight average) generally rangedfrom 10,000 to 250,000, as determined by GPC in tetrahydrofuran andcalibrated with polystyrene standards. No significant or detectablechange of molecular weight was recorded with the polycarbonates used,before and after fabrication.

f. Most of the protheses were cut to the desired lengths while still onthe mandrel. Before demandreling, the protheses were soaked in methanolor methanol/water or water for an hour in the refrigerator. This helpedto remove the protheses off the mandrel and demandreling was performedin a Class 100 laminar flow hood and handled with clean room gradegloves.

g. Sterilization was generally performed with ethylene oxide at roomtemperature.

In this manner, nerve channels from random or block copolymers of TMCand lactides were prepared.

EXAMPLE 15 Tendon and Ligament Replacement Devices

Tendon and ligament replacement devices can be fabricated from thesebiopolymer fibers by the following techniques.

A. Uniaxial towed fiber device

A bundle of well aligned fibers roughly with cross-sectional dimensionsof 5-6 mm by 0.4-0.5 mm and with a length of 45 cm are fastened onto twosurgical needles. The device is cleaned with 0.05% Trinton X-100 in 50%ethanol-water, then rinsed six times with water, and finally rinsed withabsolute alcohol. The operation is performed inside a class 100 laminarflow hood from the cleaning of the device up to and including packagingof the device in sterilization bags. Room temperature ethylene oxide isused to sterilize these devices.

The device of this size is useful for tendon or ligament replacements insmall animals, e.g., the Achilles tendon in rabbits.

B. Coated uniaxial towed fiber devices

A bundle of 44 yarns of a 220 denier yarn, made from a 5 denier perfilament fiber with tensile strength of 2.83 g/d and spun from a 98%DMTMC-2% TMC random copolymer, was cleaned by ultrasonic bath with 0.05%Triton X-100 water-ethanol solution. It was rinsed thoroughly indeionized water, and then with absolute alcohol. After air drying in alaminar flow hood, the yarn was coated with a 7% DMSO solution of 91%TMC-9% l-lactide random copolymer of MW˜87,000. The yarn was coated bydipping into the solution. After air drying (over 7 hrs.), it wasinverted and dip coated for a second time. Coating weight gain wasdetermined to be 6%. For insertion of the two ends of the prosthesisthrough the eye of the surgical needle, the ends were coated four moretimes with the solution so that the individual filaments cannot bereadily separated. After thorough air drying, the prosthesis was placedin a sterilization pack and sterilized with ethylene oxides. Theprothesis made was ready for rabbit Achilles tendon replacement.

C. Coated unaxial towed fiber devices

Similarly, a coated device of the 91% TMC 9% l-lactide coating a highstrength (extended chain) polyethylene fiber was constructed. A bundleof 14 Spectra 1000 medical grade extended chain polyethylene yarn (650denier yarn) was cleaned and dried as above. A 0.3% tetrahydrofuransolution of the 91% TMC-9% l-lactide copolymer was used for dip coating.Dip coating twice allowed a weight gain of 3% which was sufficient tohave most of the filaments adhere together but the prothesis was notcoated too heavily to become rigid and kink. The two ends were alsocoated extra for ready needle insertion. After air drying andsterilization with ethylene oxide, the prosthesis made was ready forreplacing the rabbit Achilles tendon.

D. Braided and crocheted fabric devices

Six yarns of twisted fibers are braided together to form a strand offabric 45 mm in length and with cross-sectional dimensions of 1 mm by 6mm. Similarly, yarns are crocheted into devices of variouscross-sectional diamter and length, depending on the end application.These fabrics are cleaned as discussed above and are to be used asreplacement devices for ligaments and tendons in small animals.

EXAMPLE 16 Nerve Channel Implantation Studies Mouse Sciatic NerveRegeneration

Adult anesthetized C57BL/6J mouse with a sciatic nerve transected hasboth the proximal stump and distal stump secured by a single 10-0 nylonsuture and inserted into a 5-6 mm length of a nerve channel tube madefrom the biopolymers of e.g. those from Example 3 or nerve channels madeas in Example 19 to give a final gap length of 3-4 mm. Postoperatively,at 6 weeks, the sciatic nerve of the animal, appropriately perfused fortissue studies, is again exposed and retransected 3 mm distal to thenerve guide tube. Nerve guides with enclosed regerated nerves are thendissected out, postfixed in 2% osmium tetroxide and processed forplastic embedding (DER, Ted Pella Inc.). Just before embedding, thetissue is usually divided into several segments for sampling at multiplecross-section levels. For most implants, five levels are sampled by onemicron sections. These levels are: proximal sciatic stump at 1 to 2 mmproximal to the implant; three levels (proximal, central, distal) withinthe tube through the original gap, and the distal stump 1 to 2 mm distalto the implant. Data obtained in the central section is used forcomparison.

The results will indicate that these channels do bioresorb and that theydo not cause scar formation. They will be as much or more vasotropicthan the poly d,l-lactide channels. In addition, the epineurium of theregenerated nerve using these nerve guides will be much thinner thanthat using the lactide guides and approximates the size of the intactnerve.

EXAMPLE 17 Assymmetric Membrance From Block Copolymer

The ABA block copolymer of Example 3, Sample No. 2, was used to preparethe asymmetric membrane. A sample of the polymer (5 g) was dissolved ina mixture of tetrahydrofuran (35 mL) and diglyme (5 mL) and protectedfrom drafts. The solvents were allowed to evaporate for about 4 hrs,then the plate was placed in an oven at 45°-50° C. overnight. Theresulting film was removed from the plate and submitted for analysis byscanning electron microscopy. This showed that the film has a tight,smooth, non-porous side (the glass side), and a highly porous reverseside. Cross section of the film shows that there are many pores andchannels thoroughout the bulk of the film except for the side of thetight skin. Films varying in thickness from about 80 to about 350 μmwere prepared in this way.

EXAMPLE 18 Fabrication of Rod and Ribbon as Internal Support inConjunction with Balloon Angioplasty

An ABA block copolymer, e.g. those from Examples 21 or 22 is extruded ataround 200° C. in the modified Instron extruder, with either a round ora rectangular die. The rod or ribbon produced is stored in a Class 100laminar flow hood for over 48 hrs., before it is cold drawn. The productis wrapped around a 2 mm diameter glass rod as mandrel, in a spiralfashion, and stabilized at both ends. Dimethyl sulfoxide is addeddropwise to the "spiral" while the mandrel was rotating at 5 RPM by amotor in a horizontal position. After several days, the product isremoved from the mandrel. The spiral form of the product is retained.This type of completely bioresorbable "spring" can be used inconjunction with balloon angioplasty to help to maintain the patency ofre-opened blood vessel, replacing clips or springs made of stainlesssteel or other materials.

EXAMPLE 19

Sample 2 from Example 3 was an ABA block copolymer with A:B ratio of30:70 and with l-LA (A block) and a 9 and 1 copolymer of TMC and d,l-LA(B block). Elastic tubes, useful as nerve channels, fallopian tubereplacements, were extruded at 200° C. similar to Example 12. Wheneverthe tubes were deliberately pinched close, they would reopenimmediately. Tube inner diameters of 0.5 to 3 mm were achieved.

EXAMPLE 20 Biopolymer Coated Polyurethane Devices

ComfaDerm KM-1422-00 (obtained from Semex Medical, Malvern, PA, USA), amedical grade foamed, flexible polyurethane coated on one side with apressure sensitive medical adhesive, was coated from the other side witha 4% DMSO solution of 90% TMC/10% l-lactide random copolymer. Once thesolution was applied evenly on the surface and subjected to 110° C.heating in an air oven, the solution soaked through the foam and,therefore coated the system, in a matter of minutes. Thorough drying forover 12 hrs afforded an evenly coated flexible foamed polyurethane baseddevice.

Similarly, dimethylacetamide solution casted thin or thick films ofpolyurethane, e.g., Pellethane 2103-80AE and Pellethane X0119-70A(obtained from Upjohn Co.), were readily coated with a 4% DMSObiopolymer coating solution. Once the casted polyurethane film iscasted, dried in an 120° C. oven, the DMSO coating solution was addedonto the film while still hot. The solution had a tendancy to adhereunevenly; however, with care in spreading the solution, and subjectingthe system to heating in the oven, and repeating the spreading andheating cycle a few times over time, e.g., one hour, even coatedsurfaces were obtained. Strong adhesion was achieved as demonstrated bypin pricking and rubbing, which did not separate the two films.

EXAMPLE 21 ABA Block Copolymer of Trimethylene Carbonate (TMC),d,l-lactic Acdi (d,l-LA) [B-block] and l-lactic Acid (l-LA) [A-block]Containing 45% TMC

An oven-dried, silanized glass 100 mL resin flask is equipped withmechanical stirrer with a glass paddle, argon inlet, a serum cap on oneport, and a glass stopper on the remaining port. To the flask are addedfreshly dried and purified TMC (22.5 g, 220 mmol), d, l-lactide (2.25 g,17.3 mmol) and 1,6-hexanediol (25 mg, 0.21 mmol). The flask is evacuatedand filled with argon several times, then immersed in an oil bath at150° C. Stirring is initiated, and after 5 mins., 30 μL of a 0.20Msolution of stannous octoate in toluene is added.

After 2.5 hrs., a sample of the viscous polymer is removed and l-lactide(25.0 g, 173 mmol) is added through one port. Stirring is stopped after3 hrs., then heating stopped after an additional hour. The polymer isremoved from the flask, dissolved in tetrahydrofuran (250 mL),precipitated into methanol (750 mL), and dried under vacuum at 50° C.

EXAMPLE 22 ABA Block Copolymer of Trimethylene Carbonate (TMC) [B-block]and l-Lactic Acid (l-LA) [A-block] Containing 50% TMC

An oven-dried, silanized glass 100 mL resin flask is equipped withmechanical stirrer with a glass paddle, argon inlet, a serum cap on oneport, and a glass stopper on the remaining port. To the flask are addedfreshly dried and purified TMC (25.0 g, 245 mmol) and 1,6-hexanediol (25mg, 0.21 mmol). The flask is evacuated and filled with argon severaltimes, then immersed in an oil bath at 150° C. Stirring is initiated,and after 5 mins., 30 μL of a 0.20M solution of stannous octoate intoluene is added.

After 2.5 hrs., a sample of the viscous polymer is removed and l-lactide(25.0 g, 173 mmol) is added through one port. Stirring is stopped after3 hrs., then heating stopped after an additional hour. The polymer isremoved from the flsk, dissolved in tetrahydrofuran (250 mL),precipitated into methanol (750 mL), and dried under vacuum at 50° C.

What is claimed is:
 1. A medical device formed totally or in part of oneor more block copolymers having at least one type of recurring monomericunit of the General Structure I: ##STR7## and having at least one typeof recurring monomeric units of the Structure II: ##STR8## wherein: n isfrom 1 to about 8; andR₁ and R₂ are the same or different and arehydrogen, alkyl or phenyl with the proviso that at least one of R₁ andR₂ is other than hydrogen.
 2. A medical device according to claim 1wherein n is 1 to about
 3. 3. A medical device according to claim 2wherein n is
 1. 4. A medical device according to claim 1 wherein R₁ andR₂ are the same or different and are hydrogen or alkyl.
 5. A medicaldevice according to claim 4 wherein R₁ and R₂ are the same or differentand are hydrogen or alkyl having from 1 to about 4 carbon atoms.
 6. Amedical device according to claim 5 wherein the recurring monomericunits of the Structure II are derived from a lactide.
 7. A medicaldevice according to claim 6 wherein the recurring monomeric units of theStructure II are derived from d-lactide, l-lactide or d,l-lactide.
 8. Amedical device according to claim 1 wherein the amount of the recurringmonomeric units of the Structure I in said copolymer is at least about75 wt. % based on the total weight of recurring monomer units.
 9. Amedical device according to claim 8 wherein said amount is at leastabout 85 wt. %.
 10. A medical device according to claim 9 wherein saidamount is from about 85 wt. % to about 99 wt. %.
 11. A medical deviceaccording to claim 10 wherein said amount is from about 90 wt. % toabout 99 wt. %.
 12. A medical device according to claim 1 wherein saiddevice further comprises a biodurable portion.
 13. A medical deviceaccording to claim 1 which further comprises one or more otherbioresorbable polymers.
 14. A medical device according to claim 1wherein said copolymer is a random copolymer.
 15. A medical deviceaccording to claim 1 wherein said block copolymer has an AB or an ABAstructure wherein A is a block of recurring monomeric units of theStructure I or of the Structure II, and B is a block of a recurringmonomeric units of the Structure I, the Structure II or a random blockor recurring units of the Structure I and II, with the proviso that whenA is composed of units of the Structure I, B is composed of units of theStructure II or is a random block, and that when A is composed of unitsof the Structure II, B is composed of units of the Structure I or is arandom block.
 16. A medical device according to claim 15 wherein saidblock copolymer is a block copolymer of the structure ABA.
 17. A blockcopolymer having at least one type of recurring monomeric units of theStructure I: ##STR9## and having at least one type of recurringmonomeric unit of the Structure II: ##STR10## wherein: n is from 1 toabout 8; andR₁ and R₂ are the same or different and are hydrogen, alkylor phenyl with the proviso that at least one of R₁ and R₂ is other thanhydrogen.
 18. A block copolymer according to claim 17 wherein n is 1 toabout
 3. 19. A block copolymer according to claim 18 wherein n is
 1. 20.A block copolymer according to claim 17 wherein R₁ and R₂ are the sameor different and are hydrogen or alkyl
 21. A block copolymer accordingto claim 20 wherein R₁ and R₂ are the same or different and are hydrogenor alkyl having from 1 to about 4 carbon atoms.
 22. A block copolymeraccording to claim 21 wherein the recurring monomeric units of theStructure II are derived from a lactide.
 23. A block copolymer accordingto claim 22 wherein the recurring monomeric units of the Structure IIare derived from d-lactide, l-lactide or d,l-lactide.
 24. A blockcopolymer according to claim 17 wherein the amount of the recurringmonomeric units of the Structure I in said copolymer is at least about75 wt. % based on the total weight of recurring monomer units.
 25. Ablock copolymer according to claim 24 wherein said amount is at leastabout 85 wt. %.
 26. A block copolymer according to claim 25 wherein saidamount is from about 85 wt. % to about 99 wt. %.
 27. A block copolymeraccording to claim 26 wherein said amount is from about 90 wt. % toabout 99 wt. %.
 28. A block copolymer according to claim 17 wherein saidblock copolymer has an AB or an ABA structure wherein A is a block ofrecurring monomeric units of the Structure I or of the Structure II, andB is a block of a recurring monomeric units of the Structure I, theStructure II or a random block or recurring units of the Structure I andII, with the proviso that when A is composed of units of the StructureI, B is composed of units of the Structure II or is a random block, andthat when A is composed of units of the Structure II, B is composed ofunits of Structure I or is a random block.
 29. A block copolymeraccording to claim 28 wherein said block copolymer is a block copolymerof the structure ABA.